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PLK1 inhibition dampens NLRP3 inflammasome–elicited response in inflammatory disease models
Marta Baldrighi, … , Ziad Mallat, Xuan Li
Marta Baldrighi, … , Ziad Mallat, Xuan Li
Published September 12, 2023
Citation Information: J Clin Invest. 2023;133(21):e162129. https://doi.org/10.1172/JCI162129.
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Research Article Cell biology Immunology Article has an altmetric score of 157

PLK1 inhibition dampens NLRP3 inflammasome–elicited response in inflammatory disease models

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Abstract

Unabated activation of the NLR family pyrin domain–containing 3 (NLRP3) inflammasome is linked with the pathogenesis of various inflammatory disorders. Polo-like kinase 1 (PLK1) has been widely studied for its role in mitosis. Here, using both pharmacological and genetic approaches, we demonstrate that PLK1 promoted NLRP3 inflammasome activation at cell interphase. Using an unbiased proximity-dependent biotin identification (Bio-ID) screen for the PLK1 interactome in macrophages, we show an enhanced proximal association of NLRP3 with PLK1 upon NLRP3 inflammasome activation. We further confirmed the interaction between PLK1 and NLRP3 and identified the interacting domains. Mechanistically, we show that PLK1 orchestrated the microtubule-organizing center (MTOC) structure and NLRP3 subcellular positioning upon inflammasome activation. Treatment with a selective PLK1 kinase inhibitor suppressed IL-1β production in in vivo inflammatory models, including LPS-induced endotoxemia and monosodium urate–induced peritonitis in mice. Our results uncover a role of PLK1 in regulating NLRP3 inflammasome activation during interphase and identify pharmacological inhibition of PLK1 as a potential therapeutic strategy for inflammatory diseases with excessive NLRP3 inflammasome activation.

Authors

Marta Baldrighi, Christian Doreth, Yang Li, Xiaohui Zhao, Emily Warner, Hannah Chenoweth, Kamal Kishore, Yagnesh Umrania, David-Paul Minde, Sarah Thome, Xian Yu, Yuning Lu, Alice Knapton, James Harrison, Murray Clarke, Eicke Latz, Guillermo de Cárcer, Marcos Malumbres, Bernhard Ryffel, Clare Bryant, Jinping Liu, Kathryn S. Lilley, Ziad Mallat, Xuan Li

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Figure 4

PLK1 interacts with NLRP3.

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PLK1 interacts with NLRP3.
(A–C) Reconstituted HEK 293T cells were used ...
(A–C) Reconstituted HEK 293T cells were used to perform co-IPs to determine the association between PLK1 and NLRP3 using full-length proteins (A), NLRP3 domains (PYD, pyrin domain; ΔPYD, pyrin domain deletion; LRR, leucine-rich repeat; ΔLRR, LRR deletion) with full-length PLK1 (B), or PLK1 domains (ΔKD, KD deletion; ΔPBD2, PBD2 deletion) with full-length NLRP3 (C). Domain structures of NLRP3 and PLK1 are shown in B and C. Whole-cell lysates were analyzed as an indication of transfection. (D) Bio-Layer interferometric analysis with immobilized, purified NLRP3 protein as the ligand and purified PLK1 protein as the analyte of different concentrations. (E and F) BMDMs were primed (100 ng/mL LPS, 5 hours) and then activated (5 mM ATP, 30 minutes). PLK1 inhibition with 3 μM cyclapolin 9 was used at the activation stage. Interaction between PLK1 and NLRP3 was detected by PLA. Scale bars: 10 μm (E), and quantification of PLA signals per cells (n = 185, 38, 150, and 88, in order from the left bar to the right bar) (F). Two-way ANOVA with Šidák’s post hoc test was used for statistical analysis. All data are the mean ± SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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